Treg-mediated immunosuppression involves activation of the Notch-HES1 axis by membrane-bound TGF-β
Marina Ostroukhova, … , rabir Ray,, Anuradha Ray
Marina Ostroukhova, … , rabir Ray,, Anuradha Ray
Published April 3, 2006
Citation Information: J Clin Invest. 2006;116(4):996-1004. https://doi.org/10.1172/JCI26490.
View: Text | PDF
Research Article Immunology

Treg-mediated immunosuppression involves activation of the Notch-HES1 axis by membrane-bound TGF-β

Abstract

Studies in humans and mice show an important role for Tregs in the control of immunological disorders. The mechanisms underlying the immunosuppressive functions of Tregs are not well understood. Here, we show that CD4+ T cells expressing Foxp3 and membrane-bound TGF-β (TGF-βm+Foxp3+), previously shown to be immunosuppressive in both allergic and autoimmune diseases, activate the Notch1–hairy and enhancer of split 1 (Notch1-HES1) axis in target cells. Soluble TGF-β and cells secreting similar levels of soluble TGF-β were unable to trigger Notch1 activation. Inhibition of Notch1 activation in vivo reversed the immunosuppressive functions of TGF-βm+Foxp3+ cells, resulting in severe allergic airway inflammation. Integration of the TGF-β and Notch1 pathways may be an important mechanism for the maintenance of immune homeostasis in the periphery.

Authors

Marina Ostroukhova, Zengbiao Qi, Timothy B. Oriss, Barbara Dixon-McCarthy, rabir Ray,, Anuradha Ray

×

Figure 1

Upregulation of cell surface expression of Notch1 on CD4+ T cells from tolerized mice.

Options: View larger image (or click on image) Download as PowerPoint
Upregulation of cell surface expression of Notch1 on CD4+ T cells from t...
Mice were exposed for 10 successive days to PBS (mice subsequently develop airway inflammation after OVA/alum immunization followed by OVA aerosol exposure) or to 1% OVA (to develop tolerance). Both groups were immunized with OVA/alum on days 21 and 27, and spleens were isolated (3). Spleens from 3 animals were pooled in each group, and CD4+ T cells were isolated and subjected to stimulation with OVA/APCs in vitro. The cells were stained for the expression of CD4, CD25, and Notch1. Since no staining was detected in the top left quadrants of the “Airway inflammation” and “Tolerance” panels, the total fluorescence value in the FL1 channel for the isotype control stain (top left and top right quadrants) was subtracted from the experimental stains to arrive at net percent-positive values of 5% and 15% for the airway inflammation and tolerance conditions, respectively. Expression of CD25 and Notch1 was determined on equal numbers of CD4+ T cells for each condition. Numbers in the dot plots denote percentages. Results shown are representative of 4 independent experiments.